Rumen stable medicament and/or nutrient compositions

ABSTRACT

MATERIAL SUCH AS MEDICAMENTS AND NUTRIENTS THAT DECOMPOSE WHEN THEY ARE FED ORALLY TO RUMINANTS BECUASE OF THEIR INSTABILITY IN THE IN VIVO RUMEN ENVIRONMENT CAN BE PROTECTED FROM THE RUMINANT ENVIRONMENT BY EFFECTIVELY COATING SUCH MATERIALS WITH SPECIAL NITROGEN-CONTAINING CELLULOSIC MATERIALS HAVING THE ABILITY TO RESIST BEING DEGRADED IN THE RUMEN, BUT ALSO HAVING THE ADDITIONAL ABILITY TO DISSOLVE IN THE IN VIVO ABOSMASAL FLUID.

Feb. 9, 1971 P. M. GRANT :TAL

. RUMEN STABLE MEDICAMENT AND/0R NUTRIENT coMPosITIoNs I Filed Sept. l0, 1968 BRA ZL ro/v FUL KERso/v PETER M. GRANT J HN WM CH United States Patent O 3,562,806 RUMEN STABLE MEDICAMENT AND/ R NUTRIENT CGMPOSITIONS Peter M. Grant, Brazelton Fulkerson, and John W. Mench,

Rochester, N.Y., assignors to Eastman Kodak 'Company, Rochester, NX., a corporation of New Jersey Filed Sept. 10, 1968, Ser. No. 758,874 Int. Cl. A61k 9/00 U.S. Cl. 424-35 26 Claims ABSTRACT 0F THE DISCLOSURE Materials such as medicaments and nutrients that decompose when they are fed orally to ruminants because of their instability in the in vivo rumen environment can be protected from the ruminant environment by effectively coating such materials with special nitrogen-containing cellulosic materials having the ability to resist being degraded in the rumen, but also having the additional ability to dissolve in the in vivo abomasal iluid.

The present invention relates to special compositions that are specially useful for preserving sensitive materials from undesired reaction when they are subjected to degradative environments. More specifically this invention relates to compositions containing a significant amount of a cellulosic material such as cellulose propionate 3-morpholinobutyrate effective in inhibiting such undesired reaction.

Methods for protecting reactive materials such as medicaments temporarily while the medicaments are exposed to environments which ordinarily tend to degrade or decompose the medicament have been known for many years. For example, certain drugs that would ordinarily react in an undesirable manner in the acidic environment of the stomach have been coated heretofore with various .materials that are resistant to the action of acids. In this manner, drugs for human consumption are sometimes protected during their passage through the stomach. The protecting coatings are selected so that, after the passage of the coated material through the stomach, the coating decomposes in the more basic environment of the intestine, thereby releasing the drugs (chemically unchanged) at the place in the body where the drug will be most effectively absorbed. Such coatings have been termed enteric coatings.

In the case of ruminants such as sheep and cattle, medicaments having enteric coating are, unfortunately, not protected from the drastic treatments afforded in the rumens of such animals. Medicaments given orally to ruminants pass directly irst into the rumen (which has a large population of microorganisms and is either neutral or slightly acidic). From the rumen the materials then pass into the more acidic abomasum, and subsequently into the animals intestine. In the case of such ruminants, many medicaments, including many desirable nutrients such as vita-mins, amino acids, and the like, are decomposed or metabolized to at least some extent in an undesirable manner in the environment of the rumen. Such decomposition makes oral treatment of ruminants with such susceptible materials either expensive or impossible. Thus, there is a denite need, particularly in the fields of veterinary medicine and ruminant nutrition, for a method whereby materials that are ordinarily degraded in the rumen environment can be administered orally to ruminants without such a high degree of degradation taking place.

It has now been discovered that materials intended to be administered orally to ruminants can be eiiectively protected from the rumen environment if the materials are first coated with a cellulosic material having the 3,562,806 Patented Feb. 9, 1971 proper characteristics. Materials having the proper characteristics are those that resist not only the extremely corrosive microorganism environment of the rumen, but also the solubilizing action of the in vivo rumen fluid (which has a pH of from about 5.5 to about 6.5 or more). The cellulosic materials that have been found particularly useful in this respect are those that are the products of the reaction of organic nitrogen-containing bases (wherein there is at least one replaceable hydrogen connected directly to a nitrogen atom; thus, HN with unsaturated cellulose derivatives such as the unsaturated cellulose ethers, unsaturated cellulose ester and unsaturated mixed ethers and esters of cellulose. For example, the unsaturated esters may be aliphatic (substituted or unsubstituted) or unsaturated mononuclear aryl and aralkyl esters of cellulose such as cellulose crotonate, cellulose oleate, cellulose cinnamate, cellulose tiglate, cellulose linoleate, or cellulose ricinoleate. The useful, unsaturated cellulose ethers can be the simple unsaturated aliphatic ethers such as allyl cellulose, vinyl cellulose, or crotonyl cellulose or of the cyclic series, as for example styryl cellulose. Not all the substituent groups on the cellulose molecule need be unsaturated. Thus, in addition to the unsaturated ester and/or ether substituents or groups, the useful cellulose molecules can contain saturated ester and ether groups, as for example acetyl, formyl, propionyl, butyryl, isobutyryl, benzoyl, methyl, ethyl, propyl, benzyl; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, or hydroxypropyl; and mixtures of any of these. Two or more unsaturated ester or ether groups and/ or two or more saturated ester or ether groups may be present in the cellulose molecules that are reacted with the organic bases as described above. Similarly unsaturated mixed ether-esters can be employed, the whole or part of either the ester or ether groups (or both) being unsaturated.

The organic bases with which the unsaturated cellulose derivatives are reacted in accordance with these procedures can be aliphatic, alkyl, aromatic, or alicyclic, and preferably should contain from 1 to about 20 carbon atoms. They can be either primary or secondary amines, with secondary amines being preferred. Still further preferred are the cyclic secondary amines such as, for example, piperidine, morpholine and the like. Typical, nonlimiting examples of useful organic bases are methylamine, ethylamine, propylamine, amylamine, hexylamine, dimethylamine, diethylamine, ethanolamine, diethanolamine, 2,2-dichloroethylamine, cyclohexylamine, benzylamine, methyl benzylamine, piperidine, morpholine, and the like.

Processes for manufacturing and stabilizing such reaction products are disclosed and described in detail in U.S. patent applications Ser. Nos. 653,645 now U.S. Pat. No. 3,514,442 and 653,646 now abandoned (the disclosures of which are incorporated by reference into the present disclosure).

Some of the most valuable medicament or nutrient compositions of the present invention are those in which the medicament or nutrient is coated with cellulose propionate 3-morpholinobutyrate having certain ratios of its .various substituents on the cellulose backbone The cellulose propionate 3-morpholinobutyrate having the properties essential for the success of the present invention are those containing ratios of propionyl, hydroxyl and morpholinobutyryl groups such that they fall within the shaded area designated A in the drawing. Particularly preferred cellulose propionate 3-morpholinobutyrates in this group are those containing from about 13 to about 30% of propionyl from about 0 to about 4 weight percent of hydroxyl, and from about 22 to about 50 weight percent of morpholinobutyryl.

The protected medicament and nutrient compositions of this invention can be used successfully when the composition consists mainly of the material to be protected, covered with a very thin continuous coating of at least one of the effective nitrogen-containing cellulosic materials (wherein the weight of the coating can represent as little as about 0.5 weight percent or less, but is preferably at least about 1 weight percent, of the total weight of the composition). It is generally preferred, in the successful practice of this invention, that the medicament and/or nutrient compositions of this invention be blends of (a) one or more medicaments and/or nutrients with (b) one or more of the effective cellulosic materials. Generally, in such blends, the effective cellulosic material(s) will represent at least about Weight percent of the total medicament compositions. Preferably, but not necessarily, the medicament or nutrient portion of the rumenstable compositions of this invention should be solid at temperatures below about 40 C. Typical, non-limiting, examples of medicaments that can be utilized in the practice of this invention include antibiotics (such as chlortetracycline, chloramphenicol, bacitracin zinc, erythromycin, oxytetracycline and the like) antibacterials, antivirals, growth stimulants, sulfonamides, anthelmintics, coccidiostats, hormones, vaccines, estrogens, androgens, steroids, tranquilizers and analgesics as well as materials that are often considered as nutrients such as carbohydrates, proteins, amino acids, vitamins and materials. For purposes of the present discussion such nutrients can be considered the equivalent of medicaments Actually, any material to which it is desired to impart protection from the rumen environment of ruminants can be effectively protected by utilizing one or more of the effective nitrogen-containing cellulose derivative as described herein.

In order to obtain coated medicaments in the practice of the present invention, one needs simply to dissolve the special cellulosic coating material in an organic solvent such as acetone, methylene chloride, ethylacetate, alcohol, alcohol mixtures, and the like, and subsequently spray the resulting solution over particles of the medicament that is to be protected. The particles generally result from simply compressing the material to be protected into a so-called unit dosage form such as a tablet or a smaller particle, several of which can be used simultaneously as a unit dose, if desired. As the solid medicament particles are tumbled in a convention pill-coating machine while the solution of the cellulosic protectant is sprayed onto the particles, and the solid particles are subsequently subjected to a moving air stream, the solvent can readily be evaporated from the surface of the particles, thereby leaving behind the desired continuous protective coating. Such particles generally have a desirable, hard shiny appearance. Other conventional methods for coating particulated medicaments and nutrients such as, for example, pore coating or fluidized bed procedures can also be used. The resulting coated medicament and/ or nutrient material is surprisingly rumen-stable. One of the reasons why it is surprising that the compositions of this invention are rumen-stable is that the rumen environment is designed specially to degrade cellulosic materials, while the protecting materials of this invention are cellulosic in nature. Thus, one would ordinarily expect the useful cellulosic materials of this invention to be unstable in the remen environment.

A surprisingly high degre of protection can also be afforded medicament materials in the rumen environment if the medicaments are physically blended, initially, with one or more of the nitrogen-containing cellulosic materials of this invention. In the preparation of such blends, the medicament can simply be admixed in a conventional stainless steel dough-mixer, for example, preferably with a small amount of solvent for the cellulosic material. Sometimes it is desirable to apply a relatively small amount of heat to the mixture of materials in the blender while the ingredients are being blended. After the medicament and the cellulosic material have been blended for at least a few minutes, the resulting blend can simply be removed from the mixer, cooled if necessary to thoroughly solidify the blend, and ground or crushed to yield particles of the desired size.

In the treatment of ruminants, the rumen-stable medicament and/ or nutrient compositions of the present invention are generally admixed with the ordinary feed that the ruminants are to consume. Therefore, improved feed compositions comprising a blend of common animal food material with a solid, particulated rumen-stable nitrogencontaining cellulosic material that can be solubilized in the presence of a strong acid (which materials have been described in detail hereinbefore), wherein the rumenstable cellulosic material is preferably one of the cellulose propionate 3-morpholinobutyrates having substituents such that it falls within the shaded area in the drawing stabilized with an antioxidant), constitutes one of the preferred embodiments of the present invention.

For some reason, the nitrogen-containing cellulosic materials that are useful in the practice of the present invention degrade spontaneously when they are exposed to air and warmed to slightly elevated temperatures (above about F.) or when they are stored under ambient conditions for an extended period of time. SuchV degradation results in the ultimate insolubilization of the material in the desired medium. It has been found, however, that although the protected compositions of the present invention have utility as rumen-stable compositions over very long periods of time when the nitrogencontaining cellulosic material, per se, is used, the shelf life of the compositions of this invention can be significantly prolonged if there is also present in such compositions an effective amount of an organic antioxidant material. (The stabilization of nitrogen-containing cellulosic materials with organic antioxidants is disclosed and described in detail in copending U.S. patent application Ser. No. 653,646.) Typical examples of organic antioxidants that can be used successfully to accomplish the desired stabilization of cellulose propionate 3-morpholinobutyrate, for example, include butylated hydroxytoluene, pmethoxyphenol, p-tertiary-butylphenol, t-butyl hydroquinone, hydroquinone, thymol, 2,5-bis(1,1-dimethylpropyl) hydroquinone and mixtures thereof. Of these, particularly preferred materials are butylated hydroxytoluene and pmethoxy phenol. Although the actual amount of organic antioxidant that is found necessary to effectively stabilize a particular nitrogen-containing cellulosic derivative will vary somewhat, depending upon such factors as the degree of stabilization desired, the particular antioxidant (or antioxidant mixture) that is utilized, and even the particular nitrogen-containing cellulosic derivative to be stabilized thereby, generally from about 0.05 to about 5 weight percent or more (and preferably from about 0.2 and about 2 weight percent), based on the weight of the nitrogen-containing cellulosic material being stabilized can be used. i

It should be understood that the cellulosic compositions of this invention need not necessarily be used in the pure state for successful results. For example, other materials (in addition to the medicament and/ or nutrient) can also be present in significant amounts in the compositions of this invention, so long as the basic protective abilities of the present cellulosic materials is not destroyed. Materials such as dyes, pigments, plasticizers (such as diethyl phthalate, triacetin, triphenyl phosphate, polyethylene glycol and the like) can be present in the protected medicaments and/or nutrients of this invention, in some instances, in amounts up to as much as 5 Weight percent or more, if desired. In one aspect of this invention; namely, that involving the use of the rumen-stable cellulosic materials as protective coatings over the material being protected, it is generally preferred that one or more plasticizers be present in the coating layers in order to give the coating improved flexibility.

In the following examples, cellulose propionate 3- morpholinobutyrate is used to illustrate the effective nitrogen-containing cellulosic materials that can be used resistant to degradation under this test. Since an acceptable material must also dissolve in a strong aqueous acid environment, the solubility of the tested materials after 10 minutes exposure in in vitro abomasal fluid (pH=2.5) is shown in Table I.

TABLE I.-EVALUATION OF POLYMERS FOR RUMEN STABLE COMPOSITIONS 1 Figures show percent of original weight recovered after exposure. 2 25% dimethylamino ethyl methacrylate, 67% methyl methacrylate, 8% ethyl acrylate. 3 15% dimethylaminoethyl methacrylate, 67% methyl methacrylate, 18% ethyl acrylate.

successfully in the medicament compositions of this in- Deacetylated chitin (of Example No. 10) consists of vention. However, it should be noted that when one or more of the other (than cellulose propionate 3-morpholinobutyrate) nitrogen-containing cellulosic materials described above (or in admixture with the cellulose propionate 3-morpholinobutyrate) is used in place of cellulose propionate 3-morpholinobutyrate in the following examples, similar surprisingly advantageous results can be obtained. In these examples, all parts are by weight unless otherwise specified.

EXAMPLE 1 Into a conventional stainless steel sigma blade mill are introduced 75,000 parts of (82% active) chlortetracycline (CTC), 25,000 parts of a blend of (1) cellulose propionate 3-morpholinobutyrate containing 2% hydroxyl, 19% propionyl, 43% 3-morpholinobutyryl, and having an average molecular weight of about 45,000, with (2) 125 parts of butylated hydroxyphenol (an antioxidant), and 125,000 parts of methylene chloride. The resulting mixture is blended for 20 minutes. The resulting thick, viscous mass is air dried to remove the methylene chloride, Whereupon it becomes solid. It is then ground to pass through a U.S. standard 16 mesh screen.

The resulting product is then blended with a complete lamb feed at the level of 20 grams of CTC per ton of feed. After 10 weeks, the average weight gain of l0 lambs fed with this feed composition has increased more than 5.5 pounds per lamb (15.8%) as compared with the weight gained by a control group of 10 lambs that had been fed the same type of treated feed, except that the CTC in the feed given to the control group was not blended with any of the nitrogen-containing cellulosic materials in accordance with the present invention.

It is particularly noteworthy that not every cellulosic material that is resistant to the action of the in vivo rumen environment is useful in the practice of this invention. (Nor is every nitrogen-containing cellulosic material useful in the practice of this invention.) Thus, whereas some materials are extremely resistant to the rumen environment, those materials are very likely to also be insoluble in the abomasum, as well as being insoluble in the remainder of the animals digestive tract. For usefulness in the practice of the present invention, however, the coating or protecting material must be resistant to the in vivo rumen environment, but must also readily dissolve in the more acidic abomasal fluid. Data set out in Table 1, below, illustrates these points. In order to obtain the data in Table 1, a piece of thin film of the material being tested is fastened inside a nylon fabric bag, which in turn is suspended for 24 hours (through a rumen cannula) inside the rumen of a living sheep. The weight of the film before and after such treatment indicates the resistance of the film to the in vivo rumen environment. An acceptable material (insofar as the successful practice of this invention is concerned) must be practically completely chains of glucosamine residues connected through l,4-,/3 glucosidic linkages. It is, therefore, analogous to cellulose which is chains of glucose residues connected through 1,4glucosidic linkages.

EXAMPLE l1 Two hundred sixty seven milligrams of granules of a blend of cellulose propionate 3-morpholinobutyrate and CTC prepared as in Example l, above (that pass through a U.S. Standard 16-mesh screen, but are retained on a U.S. Standard 60-rnesh screen) containing 75% CTC and 25% cellulose propionate 3-morpholinobutyrate are administered abomasally to a live sheep via abomasal cannula. As a control, 200 mg. of CTC are administered in the same manner (but without the cellulose propionate 3-morpholinobutyrate) to a second live sheep. Urine is continually collected through a urethral catheter. It is then analyzed for CTC. Practically the same amount of CTC is recovered from both sheep, indicating that CTC is readily and effectively released in the in vivo abomasal iluid from compositions of the present invention.

It should be noted that, whereas the medicament compositions described above are stable when they are subjected to the rumen environment and also will dissolve in an aqueous acidic solution having a pH below about 5, the utility of the coated compositions and blends described hereinbefore is not at all limited to application to ruminants. Thus, it has been discovered that the medicament compositions of this invention demonstrate an effectively prolonged storage life when the compositions are exposed to relatively higher temperatures and humid atmospheres. Hence, the coating procedures and blending procedures described above are useful in conjunction with any material that will ultimately be exposed to an aqueous acidic environment (such as is present in the stomach of any animal, including man) and for which is a desire to improve the stability of the material to be protected either when the material is exposed to human conditions or when it is exposed initially to alkaline, neutral, or slightly acidic environments.

EXAMPLE 12 Fifteen hundred parts of cellulose propionate 3- morpholinobutyrate (having 1.75 propionyl groups and 1.25 morpholinobutyryl groups per anhydroglucose unit and stabilized with 0.7 weight percent of butylated hydroxytoluene) and 375 parts of diethyl phthalate (plasticizer) are dissolved in 10,0100 parts of a solvent blend of acetonezmethylene chloridezethanol in weight ratios, respectively of 35 960:5. This solution is divided into ten equal portions, each of which is poured gradually over 50,000 parts of deep concave 11/32 inch core tablets of compressed dicalcium orthaphosphate, while the tablets are slowly stirred. After each portion of solution is poured onto the tablets, the solvent is evaporated therefrom by stirring the tablets continuously in a dry, cool air stream.

After 10 coats, the resulting coated tablets have an excellent, smooth appearance. The tablets do not dissolve or disintegrate in water at room temperature, even after 2 hours such exposure. However, they dissolve readily (in less than 2 minutes) in fresh abomasal uid from a sheep and in U.S.P. simulated gastric fluid.

EXAMPLE 13 Two hundred parts of cellulose propionate 3-morpholinobutyrate (having 1.55 propionyl units, 1.05 morpholinobutyryl units and 0.4 hydroxyl units per anhydroglucose unit and stabilized with 0.5 weight percent of ptertiary butylphenol) and 30 parts of diethyl phthalate (plastisizer) are dissolved in 350 parts of methylene chloride. The resulting solution is sprayed gradually onto 6700 parts of dicalcium phosphate deep concave tablets in a conventional tablet coating pan. When finish dried, the resulting tablets are found to have the type of smooth, hard, glossy finish that is considered to be very desirable as a tablet coating uish by the pharmaceutical trade. These tablets do not disintegrate or dissolve in water at room temperature, even though they are stored in contact with water for one week. They can be dissolved in U.S.P. simulated gastric fluid in only one minute, however.

EXAMPLE 14 Six parts of the cellulose propionate 3-morpholinobutyrate used in Example 13 is dissolved in 50 parts of methylene chloride. Into this solution is mixed 1 part of powdered chlortetracycline hydrochloride. The resulting slurry is then permitted to dry at room temperature. `It is then a hard plaque. It is ground into 12/ 30 mesh size granules. These granules release only 2% of their medicament into water in 24 hours, but dissolve completely in U.S.P. simulated gastric fluid in only 2 minutes, completely releasing the medicament into the gastric fluid.

The invention has been described in detail with particular reference to a preferred embodiment thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention as described hereinabove and as dened in the appended claims.

We claim:

1. A rumen-stable composition which is protected from degradation when said composition is passed through the rumen of a ruminant and which is soluble in abomasal fluid, said composition comprising:

(a) a material selected from the group consisting of oral medicaments, nutrients and mixtures thereof, and coated with (b) a nitrogen-containing derivative of cellulose; said nitrogen-containing derivative of cellulose being a product from the reaction of an unsaturated derivative of cellulose selected from the group consisting of unsaturated cellulose esters, unsaturated cellulose ethers and unsaturated cellulosic mixed ether-esters, with an organic base containing at least one H-N group in its molecule.

2. A rumen-stable composition as in claim 1, wherein said composition also contains an amount of an antioxidant; said amount being eifective to inhibit the spontaneous degradation of said nitrogen-containing derivative of cellulose.

3. A rumen-stable composition as in claim 2, wherein said nitrogen-containing derivative of cellulose is a cellulose propionate 3-morpholinobutyrate.

4. A rumen-stable composition as in claim 3, wherein said composition contains at least about 10 weight percent of said cellulose propionate 3-morpholinobutyrate, based on the combined weight of (a) and (b), and (a) and (b) are uniformly admixed in said composition.

5. A rumen-stable composition as in claim 3, wherein said cellulose propionate 3 morpholinobutyrate has a composition that falls within the area designated A in the drawing.

6. A rumen-stable composition as in claim 3, wherein said cellulose propionate 3-morpholinobutyrate contains from about 13 to about 30 weight percent propionyl, from about 22 to about 50 weight percent morpholinobutyryl, and from about 0 to about 4 weight percent hydroxyl.

7. A rumen-stable medicament composition as in claim 6, wherein said medicament is an antibiotic.

8. A rumen-stable medicament composition as in claim 6, wherein said antibiotic is chloramphenicol.

9. A rumen-stable medicament composition as in claim 6, wherein said antibiotic is chlortetracycline.

10. A rumen-stable medicament composition as in claim 6, wherein said antibiotic is oxytetracycline.

11. A rumen-stable medicament composition as in claim 6, wherein said antibiotic is erythromycin.

12. A rumen-stble medicament composition as in claim 6, wherein said antibiotic is bacitracin zinc.

13. A rumen-stable nutrient composition as in claim 20 5, whereupon said nutrient is selected from the group consisting of carbohydrates, proteins, amino acids, vitamins, minerals, and mixtures thereof.

14. A rumen-stable nutrient composition as in claim 13 wherein said nutrient is vitamin A.

15. A rumen-stable composition as in claim 3, wherein said cellulose propionate 3-morpholinobutyrate is present as an external coating over said material and in an amount equal to at least about 0.5 Weight percent.

16. An improved feed composition comprising a blend of (a) common animal food material coated with (b) a solid, particulated, rumen-stable composition that is soluble in an aqueous solution having a pH below about 5; said rumen-stable composition comprising:

(i) a material selected from the group consisting of medicaments, nutrients and mixtures thereof, and coated with (ii) a nitrogen-containing derivative of cellulose; said nitrogen-containing derivative of cellulose being a product from the reaction of an unsaturated derivative of cellulose selected from the group consisting of unsaturated cellulose esters, unsaturated cellulose ethers and unsaturated cellulosic mixed ether-esters, with an organic base containing at least one H-N group in its molecule.

17. An improved feed composition as in claim 16, wherein said nitrogen-containing derivative of cellulose is stabilized cellulose propionate 3-morpholinobutyrate.

18. An improved feed composition as in claim 17, wherein said material to be protected from direct contact with rumen fluids is a medicament.

19. An improved feed composition as in claim 17, wherein said material to be protected from direct contact with rumen fluids is a nutrient.

20. A coated composition comprising:

(a) a core material selected from the group consisting of oral ruminant medicaments, nutrients and mixtures thereof, and coated with (b) a coating material; said coating material comprising at least one rumenstable nitrogen-containing cellulosic derivative; said nitrogen-containing cellulosic derivative being a product vfrom the reaction of an unsaturated derivative of cellulose selected from the group consisting of unsaturated cellulose esters, unsaturated cellulose ethers and unsaturated cellulosic mixed ether-esters with an organic base containing at least one H-N group in its molecule.

21. A coated composition as in claim 20, wherein said nitrogen-containing cellulosic derivative is stabilized to inhibit spontaneous degradation by the presence in said coating material of an effective amount of an antioxidant, and said nitrogen-containing cellulosic derivative is present in said coated composition in an amount equal to at least about 1 weight percent.

22. A coated composition as in claim 21, wherein said nitrogen-containing cellulosic derivative is cellulose 10 propionate 3-morpho1inobutyrate having a composition References Cited that falls within the area designated A in the drawing.

23. A coated composition as in claim 22, wherein said UNITED STATES PATENTS coating material also contains at least one plasticizer. 2,196,758 4/1940 Hiatt 424 35 Z4. A coated composition as in claim 2-1, wherein said 5 2,940,901 6/1960 Hiatt et aL 424 35 organic base is a secondary amine.

25. An improved feed composition as in claim 16, SHEP K, ROSEa Primary Examiner wherein said organic base is a secondary amine.

26. A rumen-stable composition as in claim 2, wherein U.S. C1. XR. said organic base is a secondary amine. 10 99-2 

